tbuckley/cabot-search huggingface dataset:
Identification of novel neutralizing determinants for protection against HCV
Authors: Garazi P. Alzua, Anne F. Pihl, Anna Offersgaard, Rodrigo Velázquez‐Moctezuma, Carlos R. Duarte Hernandez, Elias H. Augestad, Ulrik Fahnøe, Christian K. Mathiesen, Henrik Krarup, Mansun Law, Jannick Prentoe, Jens Bukh, Judith M. Gottwein
Journal: Hepatology (2022)

Background and Aims: HCV evasion of neutralizing antibodies (nAb) results in viral persistence and poses challenges to the development of an urgently needed vaccine. N‐linked glycosylation of viral envelope proteins is a key mechanism for such evasion. To facilitate rational vaccine design, we aimed to identify determinants of protection of conserved neutralizing epitopes. Approach and Results: Using a reverse evolutionary approach, we passaged genotype 1a, 1b, 2a, 3a, and 4a HCV with envelope proteins (E1 and E2) derived from chronically infected patients without selective pressure by nAb in cell culture. Compared with the original viruses, HCV recombinants, engineered to harbor substitutions identified in polyclonal cell culture–passaged viruses, showed highly increased fitness and exposure of conserved neutralizing epitopes in antigenic regions 3 and 4, associated with protection from chronic infection. Further reverse genetic studies of acquired E1/E2 substitutions identified positions 418 and 532 in the N1 and N6 glycosylation motifs, localizing to adjacent E2 areas, as key regulators of changes of the E1/E2 conformational state, which governed viral sensitivity to nAb. These effects were independent of predicted glycan occupancy. Conclusions: We show how N‐linked glycosylation motifs can trigger dramatic changes in HCV sensitivity to nAb, independent of glycan occupancy. These findings aid in the understanding of HCV nAb evasion and rational vaccine design, as they can be exploited to stabilize the structurally flexible envelope proteins in an open conformation, exposing important neutralizing epitopes. Finally, this work resulted in a panel of highly fit cell culture infectious HCV recombinants.
Advances in extracellular vesicle functionalization strategies for tissue regeneration
Authors: Dandan Zheng, Huitong Ruan, Wei Chen, Yuhui Zhang, Wenguo Cui, Hao Chen, Hongxing Shen
Journal: Bioactive Materials (2022)

Extracellular vesicles (EVs) are nano-scale vesicles derived by cell secretion with unique advantages such as promoting cell proliferation, anti-inflammation, promoting blood vessels and regulating cell differentiation, which benefit their wide applications in regenerative medicine. However, the
Assessing Hospital-Associated Deaths From Discharge Data
Authors: Stephen F. Jencks
Journal: JAMA (1988)

To assess the meaning of hospital-associated death rates, we studied whether mortality within 30 days of hospital admission (30-day mortality) is more informative than inpatient mortality and whether detailed assessment of additional discharge diagnoses helps in understanding death rates. We examined hospitalizations for elderly Medicare patients with principal diagnoses of stroke, bacterial pneumonia, myocardial infarction, and congestive heart failure; these conditions account for 30.8% of Medicare 30-day mortality. Average hospital stays for these conditions were 99.0% longer, and inpatient mortality was 25.0% higher in New York than in California, but 30-day mortality was 1.6% higher in California. We conclude that inpatient death rates depend on length-of-stay patterns and give a biased picture of mortality. Additional diagnoses such as shock and pneumonia were strongly associated with increased mortality, but Medicare data do not reveal which patients had these conditions at the time of admission. Recorded diagnoses of chronic diseases such as hypertension, diabetes mellitus, obesity, benign prostatic hypertrophy, and osteoarthritis were commonly associated with<i>reduced</i>risk of death; such reduced risk is not clinically plausible. Several lines of evidence suggest that chronic disorders are underreported for patients with life-threatening disorders. We recommend great caution in using discharge diagnoses of comorbid conditions to adjust hospital death rates for clinical differences in the patient populations. (<i>JAMA</i>1988;260:2240-2246)
Serum Total Cholesterol and Long-term Coronary Heart Disease Mortality in Different Cultures
Authors: W. M. Monique Verschuren
Journal: JAMA (1995)

<h3>Objective.</h3> —To compare the relationship between serum total cholesterol and long-term mortality from coronary heart disease (CHD) in different cultures. <h3>Design.</h3> —Total cholesterol was measured at baseline (1958 through 1964) and at 5- and 10-year follow-up in 12 467 men aged 40 through 59 years in 16 cohorts located in seven countries: five European countries, the United States, and Japan. To increase statistical power six cohorts were formed, based on similarities in culture and cholesterol changes during the first 10 years of follow-up. <h3>Main Outcome Measures.</h3> —Relative risks (RRs), estimated with Cox proportional hazards (survival) analysis, for 25-year CHD mortality for cholesterol quartiles and per 0.50-mmol/L (20-mg/dL) cholesterol increase. Adjustment was made for age, smoking, and systolic blood pressure. <h3>Results.</h3> —The age-standardized CHD mortality rates in the six cohorts ranged from 3% to 20%. The RRs for the highest compared with the lowest cholesterol quartile ranged from 1.5 to 2.3, except for Japan's RR of 1.1. For a cholesterol level of around 5.45 mmol/L (210 mg/dL), CHD mortality rates varied from 4% to 5% in Japan and Mediterranean Southern Europe to about 15% in Northern Europe. However, the relative increase in CHD mortality due to a given cholesterol increase was similar in all cultures except Japan. Using a linear approximation, a 0.50-mmol/L (20-mg/dL) increase in total cholesterol corresponded to an increase in CHD mortality risk of 12%, which became an increase in mortality risk of 17% when adjusted for regression dilution bias. <h3>Conclusion.</h3> —Across cultures, cholesterol is linearly related to CHD mortality, and the relative increase in CHD mortality rates with a given cholesterol increase is the same. The large difference in absolute CHD mortality rates at a given cholesterol level, however, indicates that other factors, such as diet, that are typical for cultures with a low CHD risk are also important with respect to primary prevention. (<i>JAMA</i>. 1995;274:131-136)
Lessons learned from recruiting into a longitudinal remote measurement study in major depressive disorder
Authors: Carolin Oetzmann, Katie M. White, Alina Ivan, Jessica Julie, Daniel Leightley, Grace Lavelle, Femke Lamers, Sara Siddi, Peter Annas, Sara Arranz Garcia, Josep Maria Haro, David C. Mohr, Brenda W. J. H. Penninx, Sara K. Simblett, Til Wykes, Vaibhav A. Narayan, Matthew Hotopf, Faith Matcham
Journal: npj Digital Medicine (2022)

Abstract The use of remote measurement technologies (RMTs) across mobile health (mHealth) studies is becoming popular, given their potential for providing rich data on symptom change and indicators of future state in recurrent conditions such as major depressive disorder (MDD). Understanding recruitment into RMT research is fundamental for improving historically small sample sizes, reducing loss of statistical power, and ultimately producing results worthy of clinical implementation. There is a need for the standardisation of best practices for successful recruitment into RMT research. The current paper reviews lessons learned from recruitment into the Remote Assessment of Disease and Relapse- Major Depressive Disorder (RADAR-MDD) study, a large-scale, multi-site prospective cohort study using RMT to explore the clinical course of people with depression across the UK, the Netherlands, and Spain. More specifically, the paper reflects on key experiences from the UK site and consolidates these into four key recruitment strategies, alongside a review of barriers to recruitment. Finally, the strategies and barriers outlined are combined into a model of lessons learned. This work provides a foundation for future RMT study design, recruitment and evaluation.
The quantitative impact of atopic dermatitis on caregivers across multiple life domains
Authors: Richard W. Kim, Kelly Barta, Wendy S. Begolka, Korey Capozza, Sanaz Eftekhari, Kathryn Tullos, Natalie Tomaszewski, Claire Snell-Rood, Katrina Abuabara
Journal: British Journal of Dermatology (2022)

Journal Article The quantitative impact of atopic dermatitis on caregivers across multiple life domains Get access Richard W. Kim, Richard W. Kim Department of Dermatology University of California San Francisco San Francisco CA USA https://orcid.org/0000-0002-1924-6575 Search for other works by this author on: Oxford Academic Google Scholar Kelly Barta, Kelly Barta Asthma and Allergy Foundation of America Landover MD USA Search for other works by this author on: Oxford Academic Google Scholar Wendy S. Begolka, Wendy S. Begolka National Eczema Association Novato CA USA https://orcid.org/0000-0001-6107-5282 Search for other works by this author on: Oxford Academic Google Scholar Korey Capozza, Korey Capozza Global Parents for Eczema Research Santa Barbara CA USA https://orcid.org/0000-0003-2201-6655 Search for other works by this author on: Oxford Academic Google Scholar Sanaz Eftekhari, Sanaz Eftekhari Allergy and Asthma Network Vienna VA USA Search for other works by this author on: Oxford Academic Google Scholar Kathryn Tullos, Kathryn Tullos International Topical Steroid Awareness Network Dacula GA USA https://orcid.org/0000-0002-0777-2025 Search for other works by this author on: Oxford Academic Google Scholar Natalie Tomaszewski, Natalie Tomaszewski Department of Dermatology University of California San Francisco San Francisco CA USA Search for other works by this author on: Oxford Academic Google Scholar Claire Snell‐Rood, Claire Snell‐Rood Division of Epidemiology and Biostatistics UC Berkeley School of Public Health Berkeley CA USA Search for other works by this author on: Oxford Academic Google Scholar Katrina Abuabara Katrina Abuabara Department of Dermatology University of California San Francisco San Francisco CA USADivision of Epidemiology and Biostatistics UC Berkeley School of Public Health Berkeley CA USA Correspondence: Katrina Abuabara. Email: katrina.abuabara@ucsf.edu https://orcid.org/0000-0002-7736-6946 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 187, Issue 6, 1 December 2022, Pages 1041–1043, https://doi.org/10.1111/bjd.21855 Published: 01 December 2022
The Chemistry of Organic Medicinal Products
Journal: JAMA (1942)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Protein Conformational Space at the Edge of Allostery: Turning a Nonallosteric Malate Dehydrogenase into an “Allosterized” Enzyme Using Evolution-Guided Punctual Mutations
Authors: Antonio Iorio, Céline Brochier-Armanet, Caroline Mas, Fabio Sterpone, Dominique Madern
Journal: Molecular Biology and Evolution (2022)

Abstract We unveil the intimate relationship between protein dynamics and allostery by following the trajectories of model proteins in their conformational and sequence spaces. Starting from a nonallosteric hyperthermophilic malate dehydrogenase, we have tracked the role of protein dynamics in the evolution of the allosteric capacity. Based on a large phylogenetic analysis of the malate (MalDH) and lactate dehydrogenase (LDH) superfamily, we identified two amino acid positions that could have had a major role for the emergence of allostery in LDHs, which we targeted for investigation by site-directed mutagenesis. Wild-type MalDH and the single and double mutants were tested with respect to their substrate recognition profiles. The double mutant displayed a sigmoid-shaped profile typical of homotropic activation in LDH. By using molecular dynamics simulations, we showed that the mutations induce a drastic change in the protein sampling of its conformational landscape, making transiently T-like (inactive) conformers, typical of allosteric LDHs, accessible. Our data fit well with the seminal key concept linking protein dynamics and evolvability. We showed that the selection of a new phenotype can be achieved by a few key dynamics-enhancing mutations causing the enrichment of low-populated conformational substates.
A shared mucosal gut microbiota signature in primary sclerosing cholangitis before and after liver transplantation
Authors: Mikal Jacob Hole, Kristin Kaasen Jørgensen, Kristian Holm, Peder R. Braadland, Malin Holm Meyer‐Myklestad, Asle Wilhelm Medhus, Dag Henrik Reikvam, Alexandra Götz, Krzysztof Grzyb, Kirsten Muri Boberg, Tom Hemming Karlsen, Martin Kummen, Johannes R. Hov
Journal: Hepatology (2022)

Several characteristic features of the fecal microbiota have been described in primary sclerosing cholangitis (PSC), whereas data on mucosal microbiota are less consistent. We aimed to use a large colonoscopy cohort to investigate key knowledge gaps, including the role of gut microbiota in PSC with inflammatory bowel disease (IBD), the effect of liver transplantation (LT), and whether recurrent PSC (rPSC) may be used to define consistent microbiota features in PSC irrespective of LT.We included 84 PSC and 51 liver transplanted PSC patients (PSC-LT) and 40 healthy controls (HCs) and performed sequencing of the 16S ribosomal RNA gene (V3-V4) from ileocolonic biopsies. Intraindividual microbial diversity was reduced in both PSC and PSC-LT versus HCs. An expansion of Proteobacteria was more pronounced in PSC-LT (up to 19% relative abundance) than in PSC (up to 11%) and HCs (up to 8%; Q FDR < 0.05). When investigating PSC before (PSC vs. HC) and after LT (rPSC vs. no-rPSC), increased variability (dispersion) in the PSC group was found. Five genera were associated with PSC before and after LT. A dysbiosis index calculated from the five genera, and the presence of the potential pathobiont, Klebsiella , were associated with reduced LT-free survival. Concomitant IBD was associated with reduced Akkermansia .Consistent mucosal microbiota features associated with PSC, PSC-IBD, and disease severity, irrespective of LT status, highlight the usefulness of investigating PSC and rPSC in parallel, and suggest that the impact of gut microbiota on posttransplant liver health should be investigated further.
Changes in Ploidy Drive Reproduction Transition and Genomic Diversity in a Polyploid Fish Complex
Authors: Meng Lu, Zhi Li, Zi-Yu Zhu, Fang Peng, Yang Wang, Xi-Yin Li, Zhong-Wei Wang, Xiao-Juan Zhang, Li Zhou, Jian-Fang Gui
Journal: Molecular Biology and Evolution (2022)

Unisexual animals are commonly found in some polyploid species complexes, and most of these species have had a long evolutionary history. However, their method for avoiding genomic decay remains unclear. The polyploid Carassius complex naturally comprises the sexual amphidiploid C. auratus (crucian carp or goldfish) (AABB) and the gynogenetic amphitriploid C. gibelio (gibel carp) (AAABBB). Recently, we developed a fertile synthetic amphitetraploid (AAAABBBB) male from C. gibelio by incorporating a C. auratus genome. In this study, we generated novel amphitriploids (AAABBB) by backcrossing the amphitetraploid male with the amphidiploid C. auratus. Whole-genome resequencing revealed the genomic changes, including recombination and independent assortment between homologs of C. gibelio and C. auratus. The fertility, sex determination system, oocyte development, and fertilization behaviors of the novel amphitriploids were investigated. Approximately 80% of the novel amphitriploid females recovered the unisexual gynogenesis ability. Intriguingly, two types of primary oocyte (with and without homolog synapsis) were discovered, and their distinct development fates were observed. Type I oocytes entered apoptosis due to improper synaptonemal complex assembly and incomplete double-strand break repair, whereas subsequent type II oocytes bypassed meiosis through an alternative ameiotic pathway to develop into mature eggs. Moreover, gynogenesis was stabilized in their offspring, and a new array of diverse gynogenetic amphitriploid clones was produced. These revealed genomic changes and detailed cytological data provide comprehensive evidence that changes in ploidy drive unisexual and sexual reproduction transition, thereby resulting in genomic diversity and allowing C. gibelio avoid genomic decay.
E-Cadherin Phosphorylation by Protein Kinase D1/Protein Kinase Cμ is Associated with Altered Cellular Aggregation and Motility in Prostate Cancer
Authors: Meena Jaggi, Prema S. Rao, David J. Smith, Margaret J. Wheelock, Keith R. Johnson, George P. Hemstreet, K.C. Balaji
Journal: Cancer Research (2005)

Abstract The cadherin family of transmembrane glycoproteins plays a critical role in cell-to-cell adhesion and cadherin dysregulation is strongly associated with cancer metastasis and progression. In this study, we report a novel interaction between protein kinase D1 [PKD1; formerly known as protein kinase C μ (PKCμ)] and E-cadherin. PKD1 is a serine/threonine-specific kinase known to play a role in multiple cellular processes including apoptosis, cytoskeleton remodeling, and invasion. Our study shows that PKD1 colocalizes with E-cadherin at cell junctions in LNCaP prostate cancer cells and coimmunoprecipitates with E-cadherin from lysates of LNCaP cells. In vitro kinase assays have shown that PKD1 phosphorylates E-cadherin. Inhibition of PKD1 activity by the selective inhibitor Gö6976 in LNCaP cells resulted in decreased cellular aggregation and overexpression of PKD1 in C4-2 prostate cancer cells increased cellular aggregation and decreased cellular motility. We also validated the PKD1 and E-cadherin colocalization in human prostate cancer tissue by confocal laser scanning microscopy. Our study has identified E-cadherin as a novel substrate of PKD1, and phosphorylation of E-cadherin by PKD1 is associated with increased cellular aggregation and decreased cellular motility in prostate cancer. Because both E-cadherin and PKD1 are known to be dysregulated in prostate cancer, our study identified an important protein-protein interaction influencing the signal transduction system associated with cell adhesion in prostate cancer.
The Lipid Accumulation Product Is Better Than BMI for Identifying Diabetes
Authors: Henry S. Kahn
Journal: Diabetes Care (2006)

aining weight is associated with diabetes risk (1-3).It may be, however, that gaining lipid is associated more specifically with the development of insulin resistance, pancreatic exhaustion, and diabetes.According to a current pathophysiological model, when available fuels exceed the adipose tissue's capacity for buffering and safe storage, lipid will be ectopically deposited in nonadipose tissues such as liver, skeletal muscle, and the pancreatic ␤-cell (4 -6).These ectopic lipid deposits are associated with lipotoxicities that in turn lead to insulin resistance and the eventual decline of ␤-cell function (7,8).To simplify the recognition of lipid overaccumulation, researchers have devised dichotomous risk markers based on waist circumference and fasting triglyceride concentration (9 -11).However, lipid accumulation, like body weight, may not be adequately described by a dichotomous index.This report explores whether a continuous "lipid accumulation product" (LAP) performs better than the continuous BMI (in kilograms divided by the square of height in meters) for identifying adults with insulin resistance, elevated glucose, and diabetes.
Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program
Authors: Carlos Jiménez, Roberta Antonelli, Mariona Nadal-Ribelles, Laura Devis-Jauregui, Pablo Latorre, Carme Solé, Marc Masanas, Adrià Molero-Valenzuela, Aroa Soriano, Josep Sánchez de Toledo, David Llobet-Navas, Josep Roma, Francesc Posas, Eulàlia de Nadal, Soledad Gallego, Lucas Moreno, Miguel F. Segura
Journal: Molecular Cancer (2022)

Abstract Background Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma.
Novel biodegradable two-dimensional vanadene augmented photoelectro-fenton process for cancer catalytic therapy
Authors: Yichu Nie, Weilang Zhang, Wenqing Xiao, Weiwei Zeng, Ting Chen, Weiqiang Huang, Xixi Wu, Yong Kang, Jinrui Dong, Wei Luo, Xiaoyuan Ji
Journal: Biomaterials (2022)